Decoding the molecular ties between vascular disease and Alzheimer's

Seeking a better understanding of vascular contributions to Alzheimer's disease, the National Institutes of Health has launched the Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease (M²OVE-AD) Consortium, a team-science venture to build a nuanced model of Alzheimer's disease that more accurately reflects its many causes and pathways. Scientists have long been interested in how the vascular system - the body's network of large and small blood vessels - may be involved in the onset and progression of Alzheimer's disease and related dementias. Scientists from diverse fields using the latest methodologies will work collaboratively towards shared goals: to dissect the complex molecular mechanisms by which vascular risk factors influence Alzheimer's disease and identify new targets for treatment and prevention.

Developed by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS), both part of NIH, the five-year, $30-million program brings together over a dozen research teams working on five complementary projects. Harnessing the power of new molecular technologies and big data analytics, the teams will make biological datasets available to the wider research community.

"Despite evidence that the brains of most Alzheimer's patients have a variety of vascular lesions, and that mid-life diabetes and high blood pressure are major risk factors for Alzheimer's, our understanding of the molecular mechanisms involved is quite limited," said NIA Director Richard J. Hodes, M.D. "M²OVE-AD will not only advance our understanding of these mechanisms, but also identify the molecular signatures - sets of genes, proteins and metabolites - that may be used as markers for disease risk or to track the effectiveness of promising therapies."

The teams will generate several layers of molecular data from brain tissue donated by deceased Alzheimer's research participants and from blood cells and plasma donated by living study participants with various types of vascular risk. They will then develop mathematical models of the molecular processes that link vascular risk factors to Alzheimer's onset and progression by combining molecular data with data on cognition, brain imaging and several measures of vascular health.

In parallel, the teams will use a number of animal models that show different vascular disease traits to tease out the molecular mechanisms linking vascular risk factors and Alzheimer's and to test the predictions made from the analyses of the human data.

"A growing body of research suggests vascular damage often contributes to Alzheimer's disease," said Roderick Corriveau, Ph.D., program director, NINDS. "This focused collaborative effort may push our understanding of Alzheimer's disease over a tipping point and facilitate the development of better treatments for those who are suffering."

M²OVE-AD builds upon the open-science approach and the big-data infrastructure established by the Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD), a precompetitive partnership between NIH, industry and nonprofit organizations to speed the discovery of promising therapeutic targets and disease biomarkers.

"Breaking down the traditional barriers to collaboration and data-sharing is key to moving the science forward, so we've ensured that the discoveries each team makes can be rapidly shared among the Consortium and the wider research community," said Suzana Petanceska, Ph.D., senior advisor for strategic development and partnerships in the NIA Division of Neuroscience. "We've also established a panel of external leading experts to help shape the direction of M2OVE-AD research and potentially, bring about new partnerships and avenues of investigation."

Projects supported by M2OVE-AD include

Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia
Guojun Bu, Ph.D., and Nilufer Ertekin-Taner, M.D., Ph.D., Mayo Clinic, Jacksonville, Florida; in collaboration with researchers at Mayo Clinic, Rochester, Minnesota; and the Icahn Institute for Genomics and Multiscale Biology, New York City, will investigate how molecular networks influence vascular risk in aging, Alzheimer's disease and other dementias. They will explore how sex differences and the Alzheimer's risk genes influence the molecular processes that lead to vascular lesions and the development of Alzheimer's. By combining the genetic profiles of postmortem brain tissue and blood samples with other molecular, clinical and pathological data, they will build a network model of the vascular mechanisms involved in Alzheimer's that may lead to therapeutic targets; the analyses of human data will also inform their development of relevant cell-based and animal models.

Interdisciplinary Research to Understand the Interplay of Diabetes, Cerebrovascular Disease and Alzheimer's Disease
José A. Luchsinger, M.D, and Adam Brickman, Ph.D., both of Columbia University, New York City, and Herman Moreno, M.D., of SUNY Downstate Medical Center, Brooklyn, will integrate studies in humans and in animal models to examine the interplay between diabetes, Alzheimer's and cerebrovascular disease. Clinical and brain imaging data of 200 middle-aged Hispanic study participants will enable the team to explore Alzheimer's biomarkers in brain images in relation to pre-diabetes and diabetes as compared with normal glucose metabolism.

Profiling of lipids in plasma will identify molecular signatures and develop models that predict risk for Alzheimer's and cerebrovascular disease, as well as identify promising targets for therapeutic targets or biomarkers. The team will also use mouse models to examine how the interaction between diabetes and Alzheimer's pathology affects the structure and function of neural circuits important to learning and memory.

The Role of Renin Angiotensin-Endothelial Pathway in Alzheimer's Disease
Ihab Hajjar M.D, and Arshed Quyyumi, M.D., Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer's. The team will examine the molecular and vascular traits of 160 participants with either normal cognition or mild cognitive impairment, a condition that may lead to Alzheimer's.

Molecular data (genomic, epigenetic and metabolomic) combined with clinical data collected over two years will be used to build a network model of the interaction between vascular dysfunction and various Alzheimer's traits. A rat model of Alzheimer's will also be used to explore the impact of hypertension on Alzheimer's.

Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer's-Type Dementias
A research team led by Rima Kaddurah-Daouk, Ph.D., Duke University, Durham, North Carolina, and Mitch Kling, M.D., University of Pennsylvania, Philadelphia, will identify and define lipidomic signatures in plasma that are associated with cardiovascular disease and cognitive changes. The team will carry out extensive profiling of plasma samples from 900 participants in the NIA-supported Alzheimer's Disease Neuroimaging Initiative and from participants in the Duke University MURDOCK Memory and Health Study. The researchers will leverage this wealth of molecular and clinical data to identify the molecular determinants involved in risk factors for Alzheimer's.

The research team led by Steven Greenberg, M.D., Ph.D., and Brian Bacskai, Ph.D., Massachusetts General Hospital, Boston, will investigate the molecular mechanisms underlying cerebral amyloid angiopathy (CAA, a common but poorly understood cerebrovascular lesion) and its impact on Alzheimer's disease. The team's approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Their investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease may lead to new molecular targets for therapeutic intervention.

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